Method of producing anti-tussive action with 2-allyloxy-benzoic acid derivatives



United States Patent 3,160,557 ll/IETHQD 0F PRODUCING ANTi-TUSSIVEACTIGN WITH 2 ALLYLQXY BENZ-(31C ACID DERIVATIVES Roland-Yves Manvernay,idiom, France, assignor to Centre European de Recherches Mauvernay,Chateau de Bar-don, Riom, Puy-de-Dorne, France No Drawing. Filed Sept.27, 1962, Ser. No. 227,656 Claims priority, application France, May 5,1962, 896,591; .lune 25, 1962, 9tl1,887 3 Claims. (Cl. 16755) Thepresent invention relates to new 2-allyloXy-benzoic acid derivatives,and more particularly to 4-chloro- Z-allyloxy-benzoic acid derivativeswhich have important pharmacological activity, particularly asanti-tussives.

It is an object of the present invention to provide new anti-tussivecompounds.

It is a further object of the present invention to provide new2-a1lyloxy-benzoic acid derivatives which have a high degree of activityas anti-tussives comparative to the anti-tussive action of codeinwithout being a drug of addiction and while having a much lowertoxicity.

It is yet another object of the present invention to provide for theproduction of the new compounds of this invention.

It is still another object of the present invention to providecompositions containing the compounds of the present invention foranti-tussive purposes, and also to provide for the use of the compoundsof the present invention to achieve an anti-tussive action.

Other objects and advantages of the present invention will be apparentfrom a further reading of thespecification and of the appended claims.

With the above and other objects in view, the present invention mainlycomprises a compound selected from the group consisting of compounds ofthe formula:

(I)CHZCH=CHZ wherein R is selected from the group consisting of andnon-toxic physiologically compatible acid addition salts thereof.

The most preferred anti-tussive compound of the present invention is4-chloro-2-allyloxy-4-N-(,B-diethylaminoethyl)-benzamide of thefollowing structural formula:

and the most preferred acid addition salt is of the hydrochloride. Itshould be noted that other acid addition salts than the hydrochloridemay be used for the purposes of the present invention, the hydrochloridebeing pre- 3,16%,55? Patented Dec. 8, 1964 ICC ferred for reasons ofeconomy, ready availability and compatibility at least equal to any ofthe other acid addition salts.

The compounds of the present invention may be mixed with any normalpharmaceutical carrier, either for peroral administration or forinjection, utilizing an antitussive effective amount of the compound,which amount is relatively low, for example as low as 12.5 mg./kg., adose of 25 mgjkg. being suflicient to eifect complete relief from thecough.

The compounds of the present invention may be produced according to thefollowing equations:

onflon OH Br on20n=on2 HClgas v COOCH: coon o ongon=orn R OH -0 OH2OH=CHS 0 C1 l I c1 c1 Esters 7 O CH2CH=CHZ \l l Amides Cl Thus, in accordancewith the present invention 2-hydroxy4-chloro-benzoic acid is reactedwith methanol to form the corresponding methyl benzoate which is thenreacted with an ally] halide such as allyl bromide to form thecorresponding 2-allyloxy-4-chloromethy1 benzoate. This latter compoundis then reacted with thionyl chloride to form the corresponding2-allyloxy-4-chloro benzoyl chloride, which compound may then bearnidated with fi-diethylaminoethyl amine to form the correspondingbenzamide wherein R is on the other hand, the benzoyl chloride may beesterified with p-diethylaminoethanol to form the corresponding esterwherein R is or with morpholinoethanol to form the corresponding esterwherein R is The following example is given to further illustrate themethod of the present invention. The scope of the invention is not,however, meant to be limited to the specific details of the example.

EXAMPLE (a) The Production of 2-Hydr0xy-4-Chl0r0-Methyl Benzoate 200 g.of 2-hydroxy-4-chloro benzoic acid and 1 liter of methanol are broughtto reflux. Dry hydrogen chlo ride gas is bubbled through the mixtureduring a time period of 8 hours. The excess of methanol is evaporated,the residue is poured into cold water, neutralized and extracted withether. After evaporation of the solvent the product is distilled undervacuum. The boiling point of the compound at 15 mm. Hg is 127 C., andthe yield is 85% of the theoretical.

(b) The Production of 2-Allyl0xy-4-ChI0r0-Methyl Benzoate The followingmixture is heated to refluxing under agitation:

4-chloro-2-hydroxy-methyl benzoate (1 mol) g 186.5

Acetone cc 350 Anhydrous potassium carbonate g 152 Redistilled allylbromide g 133 At the end of 6 hours the reaction is completed. Thereaction mixture is filtered for removal of the mineral salts. Theacetone is evaporated. There is thus obtained an oily residue whichrapidly crystallizes. After recrystallization from methanol the productwhich is obtained is a Well crystallized white product which melts at 56C. The yield is 84%.

(c) The Production of 2-AIlyl0xy-4-Chl0roBenz0yl Chloride can be fiutherused without preliminary distillation.

(d) Preparation of the Amide and of the Hydrochloride 115.5 g. (0.5 mol)of the benzoyl chloride produced under above is dissolved in 500 cc. ofanhydrous chloroform. There is added to this solution drop by drop whileagitating and under cooling in an ice bath 116 g. of,B-diethylaminoethylamine. After the addition is completed the agitationis continued for 1 hour at ambient temperature. The reaction mass isthen washed with water, the chloroform is evaporated, the residue istaken up the minimum of absolute alcohol, and there is then added aslight excess of absolute alcohol saturated with hydrogen chloride. Thehydrochloride crystallizes by the addition of anhydrous ether. Afterrecrystallization in absolute alcohol plus ether there is obtained whitecrystals which are soluble in water and in alcohol. The2-allyloxy-4-chloro-N-(B diethylaminoethyl) benzamide hydrochloridemelts at 125l27 C.

The esterification of the 2-allyloxy-4-chloro-benzoyl chloride with,B-diethylamino ethanol or morpholino ethanol may be accomplished innormal manner and the hydrochloride or other acid addition product mayalso be produced in normal manner similar to the above production of theamide and its hydrochloride.

As indicated above, the compounds of the present invention areanti-tussive compounds which are unrelated to the morphines and theirderivatives. Studies have shown that these compounds in comparison tocodein phosphate possess a considerably lowerto-xicity while having animportant anti-tussive action without any depressive action on thecentral respiratory systemand without any depressive action onintestinal motility. In addition, these compounds have ananti-histaminic activity without having any notable deleterious sideeffects.

The following test results carried out on 2-a1lyloxy-4-chloro-N-(,B-diethylaminoethyl)-benzamide and compar- 4- ing the samewith codein illustrates the superior properties of the compounds of theinvention.

In the further discussion of pharmacological tests which follows belowthe compound of the present invention which was tested was2-allyloxy-4-chloro-N-(,B-diethylaminoethyl)-benzamide-hydrochloride,and for convenience this compound will in the further discussion whichfollows be referred to as 264 C.E.

The LD on mice was determined by the method of Behrens and Karber. Theproduct tested was administered in increasing doses on lots of 6 animalswhich were then observed for 48 hours. Under these conditions it wasfound that the LD intravenously, of the compound is 61 mg./kg. withappearance of first deaths at between 50 and mg./kg. The LD upon peroraladministration is 740 mg./kg. with appearance of the first deaths atbetween 250 and 400 mg./kg. (one death in six occurring at 400 rug/kg).

The LD of codein (phosphate) upon oral administration to mice varies,according to different authors, at between 470 and 650 mg./kg. However,the LD upon intravenous administration is mg./ kg.

The anti-tussive action was determined by the technique of Domcnjoz byelectrical excitation of the superior laryngeal nerve of the cat. Theproduct was administered intraduodeneally with increasing doses. It wasfound that at a dose of 12.5 trig/kg. the action of 264 C.E. is clearbut irregular. At a dose of 25 mg./kg. its action is marked withcomplete abolition of the cough.

This anti-tussive action, which starts 5 to 10 minutes afteradministration of the compound, persists for about 1 hour and is notaccompanied by any respiratory depression.

Codein phosphate, under the same experimental conditions, possesses acomparable anti-tussive action at a dose or" 5 mg./kg. uponintraduodenal administration, but it is necessary to increase the doseto 19 mtg/kg. intraduodenally to regularly obtain a complete abolitionof the cough. Most important, its anti-tussive action is accompaniedwith a considerable reduction in the respiratory rhythm.

The anti-histamine action was determined by two methods: the techniqueof Magnus on the terminal ileon of guinea pigs and by a modified Konzetttechnique on anesthetized guinea pigs studying the histaminicbronchoconstruction. Both methods showed 264 C.E. to have ananti-histaminic action.

Of great importance it was determined that 264 C.E. does not cause anymodification of the intestinal peristalsis, contrary to codein and othermorphine derivatives. Compositions containing the active agents ofthe'present invention can be prepared in the form of liquids, forexample syrups, tablets, dragees, suppositories and the like.-

In the case of liquids the concentration of active ingredient is mostpreferably 1 g. per liter, with the dosage being 3 to 4 tablespoons perday. In the case of tablets, using normal pharmaceutical excipients eachtablet contains 25 to 50 mg, with the -dosase being 1 to 6 tablets perday. Suppositories may be prepared with =10, 25 or 50 mg. of activeingredient per suppository, the dosage being 1 to 2 suppositories per 24hours.

Without further analysis, the foregoing will so fully reveal the gist ofthe present invention that others can by applying current knowledgereadily adapt it for various applications without omitting featuresthat, form the standpoint of prior art, fairly constitute essentialcharacteristics of the generic or specific aspects of this inventionand, therefore, such adaptations should and are intended to becomprehended within the meaning and range of equivalence of thefollowing claims.

What is claimed as new and desired to be secured by Letters Patent is:

1. The method of achieving an anti-tussive action which comprisesadministering to a patient requiring the 5 6 same a compound selectedfrom the group consisting of and non-toxic, physiologically compatibleacid addition compounds of the formula: salts thereof.

2. The method of achieving an anti-tussive action which C1-C0R comprisesadministering to a patient requiring the same 5 2-ally1oxy-4- chloro-N-fi-diethylaminoethyl) -benzamide.

F 2 3. The method of achieving an anti-tussive action which wherein Risselected from the group consisting of comprises admmlstfil'mg a P2111entrequlflng the 531116 2-a1lyloxy-4-chloro-N-(fi-dlethylaminoethyl)benzarmdezEn hydrochloride. -NH(CHz)zN 10 References Cited in the fileof this patent C H5 UNITED STATES PATENTS 2'694 088 Sahyun et a1. Nov. 91954 o CH N 2,895,992 Ohnacker et a1 July 2-1, 1959 CZHE' 15 2,937,118Von Haxthausen et a1. May 17, 1960 and 3,063,902 Gray et a1. Nov. 13,1962 3,070,628 Lemin Dec. 25, 1962

1. THE METHOD OF ACHIEVING AN ANTI-TUSSIVE ACTION WHICH COMPRISESADMINSTERING TO A PATIENT REQUIRING THE SAME A COMPOUND SELECTED FROMTHE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA: